Acylated derivatives of melationin and its analogues, useful as medicaments

ABSTRACT

The invention relates to derivatives of general formula I ##STR1## as defined in the description. The invention also relates to a process for their preparation and to their therapeutic use, in particular or the treatment of complaints associated with melatonin disorders, and pharmaceutical and cosmetic compositions comprising them.

The present invention relates to novel melatoninergic agonistderivatives, to a process for their preparation and to their use asmedicinal products.

Melatonin, N-acetyl-5-methoxytryptamine, is a hormone of the pinealgland, isolated by Lerner et al. (J. Am. Chem. Soc. 80, 1958, 2587),which has formed the subject of many studies for its circadian activity,in the rhythm of sleep, for its effects on the production oftestosterone, for its activity on the hypothalamus and in psychiatricdisorders.

It has thus been envisaged to employ melatonin and analogues thereof,especially for the treatment of depression and psychiatric disorders, inparticular stress, anxiety, depression, insomnia, schizophrenia,psychosis and epilepsy, and also for the treatment of sleeping disordersassociated with travelling ("jet lag"), neurodegenerative diseases ofthe central nervous system such as Parkinson's disease or Alzheimer'sdisease, for the treatment of cancers, or alternatively as acontraceptive or as an analgesic.

However, the direct use of melatonin in vivo has not proved to be verysatisfactory, given that a first passage through the liver extracts morethan 90% of the active principle when it is administered orally.

Various melatonin analogues have been described, demonstrating tworoutes of research which relate either to the substituents of melatonin(WO-A-89/01472, U.S. Pat. No. 5,283,343, U.S. Pat. No. 5,093,352 orWO-A-93/11761) or to the aromatic ring by replacing the indolyl group bya naphthyl group (FR-A-2 658 818, FR-A 2 689 124).

The present patent application proposes a novel route of development ofmelatonin analogues having improved activity.

The present invention thus relates to novel derivatives of generalformula I ##STR2## in which w represents an oxygen or sulphur atom or aradical ═NR₁₂, R₁₂ being a hydrogen atom or a lower alkyl, aryl, loweraralkyl or cycloalkyl radical

X represents a divalent radical of formula N--R7 or --CR₁₃ ═CR₁₄ -- orCR₁₅ R₁₆ --CR₁₇ R₁₈ --

YZ represents a trivalent radical of formula CR8═C, CW--CR₁₉, W havingthe same definition as above or CR₂₀ R₂₁ --CR₁₉

or

X--YZ represents --CR₁₅ R₁₆ --CR₂₂ ═CR₁₃ --CR₁₉ or --CR₁₅ R₁₆ --CW--CR₂₄R₂₅ --CR₁₉, or --CR₁₅ R₁₆ --CR₁₇ R₁₈ --CW--CR₁₉ W having the samedefinition as above

n represents an integer between 1 and 4, preferably 2,

R1 to R6, R15 to R21, R24 and R25 representing, independently of eachother, a hydrogen atom, a hydroxyl radical or a lower alkyl, cycloalkyl,lower alkoxy, aryloxy, lower aralkoxy, (lower)alkylthio, arylthio,(lower)aralkylthio, halo or nitro radical or an unsaturated aliphatic,lower alkenyl, lower alkinyl, lower alkyl, aryl or aralkyl chain, eachoptionally substituted with one or more hydroxyls, with one or morehalogens, a lower perhaloalkyl radical, an amino, (lower)alkylamino,(lower)dialkylamino, arylamino, diarylamino, aralkylamino orarylalkylamino radical, a radical of the form CV--R₁₁ or QCVR₁₁, inwhich V represents an oxygen or sulphur atom or an imine radical═N--R₁₂, R₁₁ has one of the meanings of R₁,

Q represents an oxygen or sulphur atom on condition that R15 and R16,R17 and R18, R20 and R21, and R24 and R25 cannot simultaneously be ahydroxyl-radical, or an amine, or a hydroxyl and an amine, a hydroxyland a halogen, or a hydroxyl and an alkoxy,

R7 has one of the meanings of R1 except that it cannot be hydroxyl, butit can represent the radical SO₂ R₂₆, R₂₆ being an alkyl or lowerhaloalkyl radical, in particular CF₃,

R13 and R14, independently of each other, have one of the meanings of R1except that when YZ represents CR₂₀ R₂₁ --CR₁₉, they cannot be an amino,(lower)alkylamino, hydroxyl, arylamino, aralkylamino or arylalkylaminoradical,

R22 and R23, independently of each other, have one of the meanings of R1except that when X--YZ is of the form CR₁₅ R₁₆ --CR₂₂ ═CR₂₃ --CR₁₉, theycannot be a hydroxyl, amino, (lower)alkylamino, arylamino, aralkylaminoor arylalkylamino radical,

R8 has one of the meanings of R1 and may also represent a halogen atom(chlorine, bromine, iodine or fluorine), or a group Q--CV--R₁₁ in whichQ, V and R11 are as defined above, or

R5 and R6 together form part of a ring of formula --(CH₂)_(m) --CW--, mbeing an integer between 2 and 3, and W defined above, on condition thatat least one of R1, R6, R7 or R8, R20, R21, R23, R24 and R25 representsa (lower)alkylcarbonyl or radical a (lower)alkylthiocarbonyl, theirracemic mixtures, their pure enantiomers or their mixtures in allproportions, and their therapeutically acceptable salts.

The present invention also relates to novel derivatives of generalformula I ##STR3## in which W represents an oxygen or sulphur atom

X represents a divalent radical of formula N--R7 or --CH═CH--

YZ represents a divalent radical of formula CR8═C,CO--CH or CS--CH

n represents an integer between 1 and 4, preferably 2,

R1, R2, R3 and R4 represent, independently of each other, a hydrogenatom, a hydroxyl radical or a lower alkyl, lower alkoxy, aryloxy, loweraralkoxy, halo or nitro radical,

R5 represents a hydrogen atom or a lower alkyl, aryl or lower aralkylradical, each optionally substituted with one or more halogens, a lowerperhaloalkyl radical, an amino, (lower)alkylamino or (lower)dialkylaminoradical or a lower alkoxy radical,

R6, R7 and R8 represent, independently of each other, a hydrogen atom, alower alkyl, aryl or lower aralkyl radical or a radical of the formCV--R11, in which V represents an oxygen or sulphur atom and R11 ahydrogen atom or a lower alkyl, aryl, lower aralkyl or cycloalkylradical, an alkyl substituted with one or more halogens, if V is anoxygen atom, R11 may also represent a lower alkoxy, a lower alkylthio,an amino radical, a (lower) alkylamino or a (lower) dialkylamino, or

R8 may also represent a halogen atom (chlorine, bromine, iodine orfluorine), a group Q--CV--R₁₁ in which Q represents an oxygen or sulphuratom, and V and R11 are as defined above, or

R5 and R6 together form part of a ring of formula --(CH₂)_(m) --CW--, mbeing an integer between 2 and 3, and W defined above, on condition thatat least one of R6, R7 or R8 represents a (lower) alkylcarbonyl radicalor a (lower) alkylthiocarbonyl, their racemic mixtures, their pureenantiomers or their mixtures in all proportions, and theirtherapeutically acceptable salts.

The expression lower alkyl, alkoxy or perhaloalkyl is generallyunderstood to refer to radicals whose alkyl residue comprises between 1and 6 carbon atoms.

These are preferably linear or branched C₁ -C₄ alkyl residues chosenmore particularly from methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl or t-butyl groups.

The term cycloalkyl refers to optionally substituted C₃ -C₆ rings.

The term aryl generally denotes aromatic and heteroaromatic groups, inparticular aryls chosen from phenyl, thienyl, furyl, pyridyl or naphthylgroups.

The aryl radicals may also be substituted with one or more substituentschosen in particular from the lower alkyl, lower alkoxy or halo radicalsdefined above.

The term lower aralkyl will be understood to refer to the combination ofa lower alkyl and an aryl as defined above. This will preferably be theoptionally-substituted benzyl radical.

The halo radicals are preferably chosen from fluorine, chlorine, bromineor iodine atoms.

The perhalo radicals are preferably perfluoro radicals.

When the derivatives according to the invention comprise at least oneasymmetric carbon of R or S configuration, the present invention alsorelates to the racemic mixtures of the general formula I, as well as itspure enantiomers, or their mixtures in all proportions.

The therapeutically acceptable salts of the derivatives according to theinvention are the usual organic or inorganic salts of the art, inparticular the hydrochlorides, tosylates, mesylates and citrates, aswell as the solvates such as the hydrates or hemihydrates of thecompounds of general formula I.

The present invention relates more particularly to the derivatives ofgeneral formula I for which W represents an oxygen atom and n is equalto 2.

Advantageously, at least one of the substituents R2 or R3 is other thana hydrogen atom and preferably represents a hydroxyl or lower alkoxyradical, in particular a methoxy radical.

R1, R4 and R6 preferably represent a hydrogen atom.

Among the preferred derivatives according to the invention, R5 isadvantageously a lower alkyl radical, preferably a methyl, an ethyl, ann-propyl or a perfluoromethyl, perfluoroethyl or perfluoropropylradical, preferably perfluoroethyl.

Advantageously, X represents the divalent radical N--R7 and R7represents a (lower) alkylcarbonyl radical.

Similarly, --YZ-- is preferably a divalent radical of formula CR8═C andR8 represents a hydrogen atom or a (lower) alkylcarbonyl radical.

When R5 and R6 together form part of a ring of formula --(CH₂)_(m)--CW--, the carbonyl or thiocarbonyl --CW-- is directly linked to thenitrogen and the radical --(CH₂)_(n) -- is, for its part, linked to thecarbonyl or thiocarbonyl of the group --CW--R5.

The present invention also relates to the process for the preparation ofthe derivatives of general formula I, as defined above.

The derivatives according to the invention may be obtained by reactingthe corresponding amine of general formula II ##STR4## X, Y, Z, n, R1 toR4 and R6 being defined above, with a suitable acylating agent,according to the usual techniques for the preparation of amides, so asto introduce the radical

    --CW--R5,

W representing an oxygen atom and R5 being defined above, with thecorresponding halide or anhydride, or alternatively with activation ofthe corresponding acid optionally with a coupling agent, as employed inpeptide synthesis.

The derivatives for which R5 and R6 together form part of a ring offormula --(CH2)_(n) --CW--, with W representing an oxygen atom, areprepared by acylating the derivative of general formula II for which R6represents a hydrogen atom, with a suitable acylating agent so as tointroduce the radical --CW--(CH₂)_(n) --CW--O-alkyl, W representing anoxygen atom and n being defined above, and then to cyclize the amideobtained by a suitable reaction, for example by acid catalysis in thepresence of traces of para-toluenesulphonic acid in xylene.

The conversion of a compound of formula I in which W represents anoxygen atom into a compound of formula I in which W represents a sulphuratom is carried out by the treatment with a standard sulphurizationreagent such as phosphorus pentasulphide or Lawesson's reagent.

The derivatives for which YZ represents a divalent radical of formula##STR5## and R8 represents a (lower) alkylcarbonyl radical, may also beprepared by hydrolysis of its cyclic precursor of general formula III##STR6## in which X, n and R1 to R5 are defined above, R9 and R10represent a hydrogen atom or a lower alkyl residue, or R9 and R10together form a cycloalkyl in order to obtain the correspondingderivative of formula I in which R6 represents a hydrogen atom, and R8represents a radical ##STR7##

The derivative obtained above may then be converted in order to obtain anovel derivative of general formula I for which R6 is other than ahydrogen atom.

Other characteristics of the derivatives according to the invention anda process for their preparation will emerge on reading the exampleswhich follow.

Starting materials

The starting materials, corresponding to the general formulae II andIII, are commercially available or may be obtained in particularaccording to the methods described below:

5-methoxytryptamine:

Supniewski et al., CA 55, 15458 (1961).

Melatonin:

Szmuskovics et al. J. Org. Chem., 25, 857 (1960),

Chem. and Eng. News, 45, 40(1967).

Serotonin and melatonin naphthalenic analogues:

Andrieux J., Anker D., Mentzer C., Chim. Ther., 57 (1966),

Yous S., Andrieux J., Howell H. E., Morgan P. J., Renard P., PfeifferB., Lesieur D., Guardiola-Lemaitre B., J. Med. Chem., 35, 1484 (1992).

N-[2-(5-methoxy-2-oxo-2,3-dihydroindol-3-yl)ethyl]-acetamide:

Szabo-Pusztay K., Szabo L, Synthesis, 276 (1979).

EXAMPLE 1 N-[2-(1-acetyl-5-methoxyindol-3-yl)ethyl]acetamide (1)

Melatonin (126 mg) is dissolved in tetrahydrofuran (10 ml) in a 50 mlround-bottomed flask, sodium hydride (200 mg) is then added and themixture is maintained at reflux (10 min). After cooling (0° C.), acetylchloride is added and the mixture is kept stirring overnight (roomtemperature). After filtration and dilution (EtOAc), the organic phaseis washed with water and then separated on a silica plate.N-[2-(1-Acetyl-5-methoxyindol-3-yl)ethyl]acetamide (1) is mainlyobtained, along with a side product,N-[2-(1-acetyl-5-methoxyindol-3-yl)ethyl]diacetamide (10) (cf. Example10).

N-[2-(1-acetyl-5-methoxyindol-3-yl)ethyl]acetamide (1)

¹ H NMR: CDCl₃ : 1.96 (s, 3H, CH₃ CO--N,); 2.49 (s, 3H, CH₃ CO--Nα);2.87 (t, 2H, CH₂); 3.56 (t, 2H, CH₂ --N); 3.84 (s, 3H, CH₃ O); 6.05(broad s, 1H, NH); 6.91 (d, 1H, H-6); 6.96 and 7.19 (2s, 2H, H-4 andH-2); 8.24 (d, 1H, H-7); MS (m/z): 274 (M.sup.⊕ ·), 215, 173, 160 (100).Exact mass: Calculated 274.1317. Found 274.1320.

EXAMPLE 2 N-[2-(2-acetyl-5-methoxyindol-3-yl)ethyl]acetamide (2)

Procedure a

1-Methylene-2-acetyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline (100 mg)is dissolved in an acidic solution (HCl, 0.1 M, 10 ml) in a 25 mlround-bottomed flask, and the mixture is heated at 60° C. for one hour.The precipitate is filtered off and then washed with ether.N-[2-(2-Acetyl-5-methoxyindol-3-yl)ethyl]acetamide (2) is thus obtained.

Procedure b

To N-[2-(5-methoxyindol-3-yl)ethyl]diacetamide (4) (35 mg) dissolved indichloromethane (3 ml), at 0° C., is added Meerwein's reagent (0.15mmol, 0.15 ml). The mixture is maintained at room temperature for 12 h.The solution is filtered. A red precipitate is obtained. The precipitateis dissolved in methanol (1 ml). After reacting for 15 min, the methanolis evaporated off and the ethyl acetate is extracted out.N-[2-(2-Acetyl-5-methoxyindol-3-yl)ethyl]acetamide (2) is thus obtained,Yield=75%.

¹ H NMR: cdcL₃ : 1.90 (s, 3H, CH₃ CO--Nβ); 3.29 (t, 2H, CH₂); 2.72 (s,3H, 2-CH₃ CO); 3.40 (t, 2H, CH₂ --N); 3.97 (s, 3H, CH₃ O); 7.11 (dd, 1H,H-6); 7.32 (broad s, 1H, NHCO); 7.39 (d, 1H, H-4); 7.47 (d, 1H, H-7);10.63 (broad s, 1H, indole NH); MS (m/z): 274 (M.sup.⊕ ·), 215 (100),202, 188, 160. Exact mass: Calculated 274.1317. Found 274.1318.

EXAMPLE 3 N-[2-(2-acetyl-5-methoxyindol-3-yl)ethyl]propionamide (3)

The procedure of Example 2 is repeated with1-methylene-2-propionyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline asstarting material.

¹ H NMR: CD₃ COOD₃ : 1.76 (t, 3H, CH₃ ethyl); 2.23 (t, 2H, CH₂ ethyl);2.72 (s, 3H, CH₃ CO in position 2 of the indole); 3.40 (t, 2H, CH₂);3.57 (q, 2H, CH₂ N); 3.95 (s, 3H, CH₃ O); 7.10 (dd, 1H, H-6); 7.20(broad s, 1H, NHCO); 7.40 (d, 1H, H-4); 7.5 (d, 1H, H-7); 10.6 (broad s,1H, NH indole); MS (m/z): 288 (M.sup.⊕ ·), 245, 215 (100), 202, 188.Exact mass: Calculated 288.1473. Found 288.1470.

EXAMPLE 4 N-[2-(5-methoxyindol-3-yl)ethyl]diacetamide (4)

Procedure a

Acetic anhydride (7 ml) is added with stirring to melatonin (500 mg)dissolved in benzene (50 ml). The mixture is heated for 72 h inrefluxing benzene. The solvent is evaporated off and the crude productis taken up in water and then neutralized with sodium carbonate solution(pH>8). After extraction (dichloromethane), washing (water) and drying(magnesium sulphate), the crude product is flash-chromatographed (EtOAceluent). N-[2-(5-Methoxyindol-3-yl)ethyl]diacetamide (4) (300 mg, 50%yield) is obtained.

Procedure b

Acetic anhydride (3 ml) is added with stirring to melatonin (380 mg) .The mixture is heated for 4 h at 145° C. After evaporation of the aceticanhydride, the crude product is flash-chromatographed (50/50EtOAc/petroleum ether eluent). The following are successively eluted:

N-[2-(5-Methoxyindol-3-yl)ethyl]diacetamide (4) (180 mg, 40% yield).

¹ H NMR: DMSO D₆ : 2.30 (s, 6H, 2 (CH₃ CO)); 2.93 (t, 2H, CH₂); 3.81 (s,3H, CH₃ O); 3.89 (t, 2H, CH₂ --N) ; 6.76 (d, 1H, H-6); 7.02 and 7.07(2s, 2H, H-2 and H-4); 7.22 (d, 1H, H-7); 10.48 (broad s, 1H, NH); MS(m/z): 274 (M.sup.⊕ ·) 173 (100), 160, 145, 77. Exact mass: Calculated274.1317. Found 274.1320.

N-[2-(2-acetyl-5-methoxyindol-3-yl)ethyl]diacetamide (9),

N-[-(1-acetyl-5-methoxyindol-3-yl)ethyl]diacetamide (10).

EXAMPLE 5

N-[2-(2-acetylindol-3-yl)ethyl]acetamide (5)

The procedure of Example 2 is repeated with1-methylene-2-acetyl-1,2,3,4-tetrahydro-β-carboline as startingmaterial.

¹ H NMR: CDCl₃ : 1.88 (t, 3H, CH₃ CO); 2.58 (s, 3H, CH₃ CO in position 2of the indole); 3.27 (t, 2H, CH, in position 3 of the indole); 3.53 (t,2H, CH₂ --N); 6.68 (broad s, 1H, NHCO); 7.08 (t, 1H, H-7); 7.32 (m, 2H,H-5 and 6); 7.61 (d, 1H, H-4); 10 (broad s, 1H, indole NH); MS (m/z):244 (M.sup.⊕ ·), 185 (100), 172, 158, 130.

EXAMPLE 6N-[2-(1-acetyl-2-oxo-5-methoxy-2,3-dihydroindol-3-yl)-ethyl]acetamide(6)

Acetic anhydride (0.5 ml) is added with stirring toN-[2-(5-methoxy-2-oxo-2,3-dihydroindol-3-yl)ethyl]-acetamide (120 mg)dissolved in benzene (5 ml). The mixture is heated for 1 h in refluxingbenzene. The solvent is evaporated off and the crude product isseparated on a silica plate.N-[2-(1-acetyl-2-oxo-5-methoxyindol-3-yl)ethyl]acetamide (6) is thusobtained.

¹ H NMR: CD₃ COOD₃ : 1.84 (s, 3H, CH₃ CO-Nβ); 2.30 and 2.94 (2m, 2H,CH₂), 2.57 (s, 3H, CH₃ CO-Nα); 3.25 and 3.47 (2m, 2H, CH₂ --N); 3.76 (t,1H, H-3); 3.80 (s, 3H, CH₃ O); 6.57 (d, 1H, H-6) ; 7.09 (s, 1H, H-4);8.03 (d, 1H, H-7); 7.22 (broad s, 1H, NH).

EXAMPLE 7 N-[2-(5-Methoxyindol-3-yl)ethyl]glutarimide (7)

A mixture of 5-methoxytryptamine (420 mg) and diethyl glutarate (460 mg)is heated at 175° C. for 18 h. Separation on a column (EtOAc eluent)gives the corresponding ester amide.

The latter is treated with a trace of paratoluenesulphonic acid inxylene and the ethanol formed is removed using Dean-Stark apparatus.After refluxing for 9 h and separation on a silica plate,N-[2-(5-Methoxyindol-3-yl)ethyl]glutarimide (7) is obtained. ¹ H NMR:CDCl₃ : 1.88 (m, 2H, CH₂ β to the 2 CO): 2.62 (t, 4H, CH₂ α to the CO);2.93 (t, 2H, CH₂ in position 3 of the indole); 3.90 (s, 3H, OCH₃); 4.05(t, 2H, CH₂ --NCO); 6.87 (dd, 1H, H-6); 7.03 (s, 1H, H-4); 7.20 (d, 1H,H-7); 8.0 (broad s, 1H, indole N--H). Mass spectrum (m/z): 286 (M.sup.⊕·), 173 (100), 160. Exact mass: Calculated 286.1317. Found 286.1310.

EXAMPLE 8N-[2-(2-Cyclohexylcarbonyl-5-methoxyindol-3-yl)ethyl]-acetamide (8)

Repeating the procedure of Example 2,N-[2-(2-cyclohexylcarbonyl-5-methoxyindol-3-yl)ethyl]acetamide (8) isobtained.

¹ H NMR: CDCl₃ : between 1.30 and 1.80 (complex multiplet, 10Hcyclohexyl); 1.91 (s, 3H, NCOCH₃); 3.30 (t, 2H, CH₂ in position 3 of theindole); 3.59 (t, 2H, CH₂ --NCO); 3.81 (s, 3H, OCH₃); 6.72 (broad s,NHCO); 6.98 (d, 1H, H-6); 7.01 (s, 1H, H-4); 7.27 (d, 1H, H-7); 9.75(broad s, 1H, indole N--H). Mass spectrum (m/z): 342 (M.sup.⊕ ·), 283(100), 268, 188.

EXAMPLE 9 N-[2-(2-Acetyl-5-methoxyindol-3-yl)ethyl]diacetamide (9)

N-[2-(2-Acetyl-5-methoxyindol-3-yl)ethyl]diacetamide (9) is a sideproduct in the acylation reaction of melatonin according to the processof Example 4, procedure B, isolated by flash chromatography.

¹ H NMR: CDCl₃ : 2.39 (s, 3H, CH₃ CO--N,); 2.58 (s, 6H, CH₃ CO--Nα);3.35 (t, 2H, CH₂ --Ar); 3.90 (s, 3H, CH₃ O); 3.90 (t, 2H, CH₂ --Nβ);6.98 (dd, 1H, H-6); 7.12 (d, 1H, H-4); 7.29 (d, 1H, H-7); 8.85 (broad s,1H, NH).

EXAMPLE 10 N-[2-(1-acetyl-5-methoxyindol-3-yl)ethyl]diacetamide (10)

¹ H NMR: CDCl₃ : 2.39 (s, 3H, CH₃ CO--Nβ); 2.58 (s, 6H, CH₃ CO--Nα);2.94 (t, 2H, CH₂); 3.89 (s, 3H, CH₃ O); 3.93 (t, 2H, CH2--N); 6.95 (dd,1H, H-6); 7.13 (d, 1H, H-4); 7.22 (s, 1H, H-2); 8.3 (d, 1H, H-5); MS(m/z) : 316 (M.sup.⊕ ·) , 215, 173 (100), 160.

EXAMPLE 11 N-[2-(5-Methoxy-2-oxo-2,3-dihydroindol-3-yl)ethyl]glutaramide (11)

145 mg of N-[2-(5-methoxyindol-3-yl)ethyl]glutarimide are dissolved inDMSO (30 μl) in a round-bottomed flask and concentrated HCl (72 μl) isadded with stirring. The mixture is stirred overnight at roomtemperature. The crude product is neutralized with NH₃ and thenextracted with EtOAc. After separation on a silica plate,N-[2-(5-methoxy-2-oxo-2,3-dihydroindol-3-yl)ethyl]-glutarimide isobtained.

¹ H NNR: CDCl₃ : 1.82, (m, 2H, CH₂ β to the 2 CO); 2.18 (2m, 2H, CH₂),2.52 (t, 4H, CH₂ a to the CO); 3.47 and 3.85 (2m, 2H, CH₂ --N); 3.78 (s,3H, OCH₃); 4.09 (t, 1H, H-3); 6.97 (m, 2H, H-6, H-7); 6.91 (s, 1H, H-4).

EXAMPLE 12 N-[2-(6-Acetyl-5-methoxyindol-3-yl)ethyl]acetamide (12)

N-[2-(6-Acetyl-5-methoxyindol-3-yl)ethyl]acetamide is prepared byalkaline hydrolysis of N-[2-(6-acetyl-1-carbethoxy-5-methoxyindol-3-yl)ethyl]acetamide in alcoholic potassium hydroxide.

¹ H NMR: CDCl₃ : 1.89, (s, 3H), 2.61 (s, 3H); 2.88 (t, 2H); 3.43 (q,2H); 3.90 (s, 3H); 6.25 (broad s, 1H); 6.95 (s, 1H); 7.06 (s, 1H); 7.76(s, 1H); MS (m/z): 274 (M⁺ ·) , 215, 202(100).

EXAMPLE 13 N-[2-(6-Acetyl-1-carbethoxy-5-methoxyindol-3-yl)ethyl]-acetamide (13)

The first step of the synthesis is a carboethoxylation of melatonin withethyl chloroformate in the presence of sodium hydroxide andtetrabutylammonium hydrogen sulphate. Acetylation of the productobtained with acetyl chloride in the presence of aluminium chloride indichloroethane leads, after hydrolysis, toN-[2-(6-acetyl-1-carbethoxy-5-methoxyindol-3-yl)ethyl]acetamide.

¹ H NMR: CDCl₃ : 1.48, (s, 3H, CH, carbamate), 1.98 (s, 3H, CH₃ amide);2.64 (s, 3H, CH, methylketone); 2.89 (t, 2H, CH₂ -indole); 3.58 (t, 2H,CH² --N); 3.95 (s, 3H, CH₃ O); 4.47 (q, 2H, CH₂ carbamate); 5.88 (broads, 1H, N--H); 6.99 (s, 1H, H-4); 7.45 (s, 1H, H-2); 8.4 (s, 1H, H-7). MS(m/z): 346 (M⁺ ·), 287 (100), 272, 202.

EXAMPLE 14N-[2-(1-carbethoxy-2-acetyl-5-methoxyindol-3-yl)ethyl]-acetamide (14)

1-Methylene-2-acetyl-9-carbethoxy-6-methoxy-β-carboline (100 mg) isdissolved in acidic solution (HCl, 0.1 M, 10 ml) in a round-bottomedflask (25 ml) and the mixture is heated at 60° C. for one hour. Theprecipitate is filtered off and then washed with ether.N-[2-(1-Carbethoxy-2-acetyl-5-methoxyindol-3-yl) ethyl]acetamide is thusobtained.

¹ NMR: CDCl₃ : 1.45 (t, 3H); 1.92 (s, 3H); 2.45 (s, 3H); 2.84 (t, 2H);3.49 (t, 2H); 3.83 (s, 3H); 4.47 (q, 2H); 7.0-7.06 (m, 3H); 7.92 (d,1H); MS (m/z): 346 (M⁺ ·), 287, 215, 202(100).

EXAMPLE 15 N-[2-(2-acetyl-6-ethyl-5-methoxyindol-3-yl)ethyl]-acetamide(14)

1-Methylene-2-acetyl-7-ethyl-6-methoxy-β-carboline (100 mg) is dissolvedin acidic solution (HCl, 0.1 M, 10 ml) in a round-bottomed flask (25 ml)and the mixture is heated at 60° C. for one hour. The precipitate isfiltered off and then washed with ether.N-[2-(2-Acetyl-6-ethyl-5-methoxyindol-3-yl)ethyl]acetamide is thusobtained.

¹ H NMR: CDCl₃ : 1.22 (t, 3H); 1.91 (s, 3H); 2.60 (s, 3H); 2.72 (q, 2H); 3.27 (t, 2H, CH₂); 3.52 (t, 2H); 3.86 (s, 3H); 6.97 (broad t, 1H);7.15 (s, 1H); 7.31 (s, 1H); MS (m/z): 302 (M⁺ ·), 243 (100), 259, 230,216.

EXAMPLE 16 N-[2-(1-acetyl-5-methoxyindolin-3-yl)ethyl]acetamide (16)

To a solution, cooled to 0° C., of melatonin (1 mmol) in trifluoroaceticacid (2 ml) is added dropwise borane (2 eq, 1M solution in THF) . Themixture is stirred for 30 min at 0° C. followed by dropwise addition ofwater (1.5 ml), and the medium is left stirring for 1 h at roomtemperature. The mixture is then brought to pH=10 using 2N potassiumhydroxide solution and is then extracted with dichloromethane. The crudeproduct is separated on a column of flash silica (25/75/5acetone/dichloromethane/methanol) and 110 mg ofN-[2-(5-methoxyindolin-3-yl)ethyl]acetamide are obtained, which productis then acetylated with acetic anhydride in pyridine to giveN-[2-(1-acetyl-5-methoxyindolin-3-yl)ethyl]acetamide.

¹ H NMR: CDCl₃ : 1.65 (m, 1H); 1.93 (s, 3H); 1.9 (m, 1H); 2.12 (s, 3H);3.31 (m, 3H); 3.63 (m, 1H); 3.68 (s, 3H); 4.11 (2m, 1H); 6.49 (broad s,1H); 6.66 (m, 2H); 8.02 (d, 1H). MS (m/z): 276 (M⁺ ·), 272, 204, 174,160, 148(100).

EXAMPLE 17 N-[2-(1-acetyl-6-chloro-5-methoxyindolin-3-yl)ethyl]acetamide (17)

To a solution of N-[2-(1-acetyl-5-methoxyindolin-3-yl)ethyl]acetamide(0.29 mmol) in acetonitrile (1.5 ml) is addedbis(trifluoroacetoxyiodobenzene) (PIFA 1.2 eq) and the medium is leftstirring for 1 min at room temperature. Saturated sodium chloridesolution (0.5 ml) is next added and, after 15 min, the mixture isdiluted with dichloromethane (10 ml) and dried over magnesium sulphate.The crude product obtained after evaporation is chromatographed on acolumn of flash silica (5/95 methanol/dichloromethane) andN-[2-(l-acetyl-6-chloro-5-methoxyindolin-3-yl)ethyl]acetamide (70 mg) isthus obtained.

¹ H NMR: CDCl₃ : 1.65 (m, 1H); 1.91 (s, 3H); 1.9 (m, 1H); 2.12 (s, 3H);3.31 (m, 3H); 3.63 (m, 1H); 3.80 (s, 3H); 4.11 (2m, 1H); 6.28 (broad s,1H); 6.75 (s, 1H); 8.15 (d, 1H).

EXAMPLE 18 N-[2-(1-benzyloxycarbonyl-5-methoxyindolin-3-yl)ethyl]-diacetamide (18)

N-[2-(5-Methoxyindolin-3-yl)ethyl]acetamide is prepared by the methoddescribed for the synthesis ofN-[2-(1-acetyl-5-methoxyindolin-3-yl)ethyl]acetamide. The intermediateN-[2-(1-benzyloxycarbonyl-5-methoxyindolin-3-yl) ethyl]acetamide isprepared by reacting the N-[2-(5-methoxyindolin-3-yl)ethyl]acetamidewith ethyl chloroformate in dichloromethane at 0° C. in the presence oftriethylamine. The final acylation is carried out with acetic anhydridein refluxing toluene for 24 h, and allowsN-[2-(1-trifluoromethanesulphonyl-5-methoxyindolin-3-yl)ethyl]diacetamideto be obtained.

¹ H NMR: CDCl₃ : 1.96 and 2.11 (2m, 2H); 2.32 (s, 6H); 3.28 (m, 1H);3.53 (m, 1H); 3.71 (s, 3H); 3.74-3.80 (m, 2H); 4.13 (m, 1H); 5.20 (m,2H); 6.72 (m, 2H); 7.35 and 7.8 (m, 6H).

¹³ C(DEPT): 26.1(CH₃); 33.7(CH₂); 37.4(CH); 42.1(CH₂); 52.8(CH₂); 55.3(CH₃); 66.6(CH₂); 110.3(CH); 112.4(CH); 115.1(CH); 127.9(CH); 128.0(CH);128.6(CH); 134.4(C); 135.7(C); 136.2(C); 155.6(C);

170.0(CO); 172.6(CO).

EXAMPLE 19 N-[2-(1-trifluoromethanesulphonyl-5-methoxyindolin-3-yl)ethyl]diacetamide (19)

N-[2-(5-Methoxyindolin-3-yl)ethyl]acetamide is prepared by the methoddescribed for the synthesis ofN-[2-(1-acetyl-5-methoxyindolin-3-yl)ethyl]acetamide. The intermediateN-[2-(1-trifluoromethanesulphonyl-5-methoxyindolin-3-yl)ethyl]acetamideis prepared by reacting N-[2-(5-methoxyindolin-3-yl)ethyl]acetamide withtrifluoromethanesulphonic anhydride in dichloromethane at -78° C. in thepresence of triethylamine. The final acylation is carried out withacetic anhydride in refluxing toluene for 24 h, and allowsN-[2-(1-trifluoromethanesulphonyl-5-methoxyindolin-3-yl)ethyl]diacetamideto be obtained.

¹ H NMR: CDCl₃ : 2.01 (m, 2H); 2.41 (s, 6H); 3.42 (m, 1H); 3.66 (m, 1H);3.79 (s, 3H); 3.86 (m, 1H); 3.95 (m, 1H); 4.36 (t, 1H); 6.79 (m, 2H);7.33 (d, 1H)

EXAMPLE 20N-[2-(6-(1-acetyl-3-(N,N-diacetyl-2-aminoethyl)-5-methoxyindolin-2-yl)-5-methoxyindol-3-yl)ethyl]diacetamide(20)

The product is prepared according to the method described by Laronze etal. (Bull. Soc. Chim. Fr. 1966, vol 133, p39-50), followed byacetylation according to the procedure described forN-[2-(5-methoxyindol-3-yl)ethyl]diacetamide.

¹ H NMR: CDCl₃ : 2.03 (s, 3H); 2.37 (s, 12H); 2.45 (m, 2H); 2.96 (t,2H); 3.0 (m, 1H); 3.73 (s, 3H); 3.78 (m, 4H); 4.00 (s, 3H); 5.59 (s,1H); 6.64 (s, 1H);

6.70 (dd, 1H); 6.88 (s, 1H); 6.93 (d, 1H); 7.19 (s, 1H); 8.25 (d, 1H);8.37 (broad s, 1H) MS (m/z): 590 (M⁺ ·), 345, 215, 173(100).

EXAMPLE 21 N-[2-(2-acetyl-7-methoxynaphth-1-yl) ethyl]acetamide (21)

N-[2-(2-Acetyl-7-methoxynaphth-1-yl)ethyl]acetamide is obtained by acidhydrolysis of6-methoxy-1-methylene-2-acetyl-2-aza-1,2,3,4-tetrahydrophenanthrene,prepared according to the method described by Jacquesy et al. (PCTpatent/Fr 95/01179).

¹ H NMR: CDCl₃ : 1.91 (s, 3H); 2.68 (s, 3H); 3.35 (t, 2H) 3.66 (q, 2H);4.03 (s, 3H); 6.86 (broad s, 1H); 7.23 (dd, 1H); 7.48 (d, 1H); 7.7 (m,3H)

EXAMPLE 22 N-[2-(carbethoxy-2-acetyl-5-methoxyindolin-3-yl)ethyl]-acetamide (22)

The productN-[2-(1-carbethoxy-2-acetyl-5-methoxyindol-3-yl)ethyl]acetamide (100 mg)is dissolved in ethanol (10 ml) in a round-bottomed flask (25 ml), 100mg of Pd(OH)₂ are added and the mixture is stirred for 12 h at a normalpressure of hydrogen. After filtration,N-[2-(1-carbethoxy-2-acetyl-5-methoxyindolin-3-yl)-ethyl]acetamide isobtained.

¹ H NMR: CDCl₃ : 1.27 (broad s, 3H); 1.50 (m, 1H); 1.92 (m, 7H); 3.45(m, 2H); 3.78 (s, 3H); 4.30 (broad s, 2H); 4.83 (d, 1H); 6 (broad s,NH); 6.77 (m, 2H); 7.79 (broad s, 1H).

    __________________________________________________________________________                                               Empirical formula                    Example Name Structural formula Molar mass                                  __________________________________________________________________________       1 1AcMela                                                                                                               C.sub.15 H.sub.18 N.sub.2                                                   O.sub.3  274.31                       -  2 2AcMela                                                                                                            C.sub.15 H.sub.18 N.sub.2                                                   O.sub.3  274.31                       -  3 2aAcMela                                                                                                           C.sub.16 H.sub.20 N.sub.2                                                   O.sub.3  288.34                       -  4 MELA3                                                                                                              C.sub.15 H.sub.18 N.sub.2                                                   O.sub.3  274.31                       -  5 2-Ac-TRYP                                                                                                          C.sub.14 H.sub.16 N.sub.2                                                   O.sub.2  244.29                       -  6 1AC-  2OXOMELA                                                                                                     C.sub.15 H.sub.18 N.sub.2                                                   O.sub.4  290.31                       -  7 MELA3G                                                                                                             C.sub.16 H.sub.18 N.sub.2                                                   O.sub.3  286.33                       -  8 2cyAcMELA                                                                                                          C.sub.20 H.sub.26 N.sub.2                                                   O.sub.3  342.43                       -  9 2Ac-MELA3                                                                                                          C.sub.17 H.sub.20 N.sub.2                                                   O.sub.4  316.35                       - 10 1Ac-MELA3                                                                                                          C.sub.17 H.sub.20 N.sub.2                                                   O.sub.4  316.35                       - 11 2-  OXOMELA3G                                                                                                      C.sub.16 H.sub.18 N.sub.2                                                   O.sub.4  302.32                       - 12 6AcMela                                                                                                            C.sub.13 H.sub.15 N.sub.2                                                   O.sub.2  274.31                       - 13 CBACMELA                                                                                                           C.sub.15 H.sub.22 N.sub.2                                                   O.sub.3  --  346.38                   - 14 CB2AcMela                                                                                                          C.sub.18 H.sub.22 N.sub.2                                                   O.sub.3  346.38                       - 15 6Et2AcMela                                                                                                         Cl.sub.7 H.sub.22 N.sub.2                                                   O.sub.3  302.37                       - 16 1AcDHMela                                                                                                          C.sub.15 H.sub.20 N.sub.2                                                   O.sub.3  276.33                       - 17 6CHAcDHMela                                                                                                        C.sub.13 H.sub.19 N.sub.2                                                   O.sub.3 Cl  310.78                    - 18 CBDHMela3                                                                                                          C.sub.23 H26N.sub.2 O.sub.3                                                 410.46                                - 19 TFDHMela3                                                                                                          C.sub.16 H.sub.19 N.sub.2                                                   O.sub.3 SF.sub.3  408.39                                                        - 20 6DMela3                                                                  C.sub.22 H.sub.35 N.sub.4                                                   O.sub.7  590.67                       - 21 2-AcNaph2                                                                                                          C.sub.17 H.sub.19 NO.sub.3                                                  285.34                                - 22 C2AcDHMela                                                                                                         C.sub.18 H.sub.24 N.sub.2                                                   O.sub.3  348.39                    __________________________________________________________________________

Biological Activity

The hypnotic and sedative effects of the derivatives according to theinvention, prepared above (whose test results are indicated in Table Ibelow), were compared with those of two reference products, diazepam andmelatonin, in 10- to 15-day-old chicks of the strain chair label JA657.The animals are subjected to programmes of alternating lightingconsisting of 12 h of darkness (8.00 pm to 8.00 am) and 12 h of light(8.0 am to 8.00 pm). The room temperature is 25° C. for the first weekthat the chicks are reared and 22° C. from the second week onwards.During the day, the light is provided by a 100W lamp placed 30 cm abovethe floor of the vivarium. During the tests, the live weight of thechicks varied between 95 and 155 g. The tests are carried out startingat 2.00 pm. The chicks are allotted into groups of 3 in identical 30cm×50 cm×30 cm vivariums. The test products are administeredintramuscularly (IM) into the pectoralis major muscle, inaqueous-ethanolic solution (ethanol/distilled water mixture, 50/50 V/V),at a rate of 0.2 ml of ethanolic solution per 100 g of live weight. Thedoses administered for the test products (novel compounds of theinvention and reference substances) are equimolar (2 μM/100 g of liveweight). The placebo corresponds to 0.2 ml of the ethanol/distilledwater mixture (aa). Since ethanol is used as solvent, its effect wascompared beforehand with that of physiological saline (NaCl solution at0.9 p.100) or distilled water.

The aqueous-ethanolic solutions of the test products were prepared atthe time of use by successive dilution of an accurately weighed stocksolution, obtained from 20 μM of product, to which is added 1 ml of pureethanol, stirred by ultrasound and then made up to 2 ml with 1 ml ofdistilled water for an injectable preparation. The results obtainedafter IM administration of 2 μm mol of the test products, as a solutionin 0.2 ml of the ethanol/distilled water mixture, per 100 g of liveweight are presented in Table I. For each chick, the volume injected isadjusted, as a function of the actual live weight, to 0.2 ml per 100 gof live weight.

The parameters observed are the locomotor activity and the state ofwakefulness of the chicks for 2 h, i.e. the equivalent of 6 theoreticalwake-sleep cycles for a chick of this age. They are recorded by videocamera over 120 minutes.

Five stages of alertness were defined:

stage 1: active wakefulness;

stage 2: prostrate animal, head maintained with tonicity, eyes open;

stage 3: light sleep, animal drowsy, eyes closed with intermittentopening, immobile posture not modified by stimulation;

stage 4: deep prostrate sleep: neck relaxed, characteristic posture withhead under the wing or hanging backwards;

stage 5: standing sleep: eyes closed, immobile, head hanging down(catatonic).

These five stages correspond approximately to the stages of alertnessand sleep defined on examining the electroencephalographic traces inthis species. The correspondence is as follows:

deep prostrate sleep: stage 4="slow wave sleep" (SWS)

standing sleep: "sleep-like state I" (SLSI)

Stage 3, drowsy, could correspond to phases of paradoxal sleep, withmovement of the head, for example.

The chicks are observed by a trained observer with continuous videocontrol for at least 1 hour after the animals have woken up.

Two stimuli were used to confirm the observations of the behaviour ofthe chicks at regular intervals:

the noise caused by the shock of a plastic object on the glass of thevivarium, comparable to that of a chick's beak on the glass, correspondsto a moderate stimulus. It is carried out at each observation period(i.e. every 5 minutes);

and the presentation of a metal feeding container filled with the usualfood, left in the vivarium for 2 minutes. This is a powerful stimuluswhich calls upon vision, hearing and smell. It is carried out every 15minutes, that is to say at least 6 times for each test.

Wakefulness is defined by the appearance of the conscious elaboratebehaviour of searching for and consuming food or drink.

The sleep time (ST) is defined by the sum of the durations of the phasesof light sleep (stage 3), deep sleep (stage 4) and standing sleep (stage5). The sedation time corresponds to the sum of the various times ofactive wakefulness during the observation period of 120 minutes.

The falling-asleep time (FAT) is equal (to within one minute) to thetime required to pass from a state of active wakefulness (stage 1) to anon-alert state (stages 3, 4 and 5).

The hypnotic and sedative effects of the test products on the diurnalactivity of 10- to 15-day-old chicks subjected to a programme ofpermanent light from birth to the 6th day, and then to a programme ofalternate lighting of 12 h of day (8.00 am-8.00 pm) and 12 h of darkness(8.00 pm-8.00 am), are reported in Table I below.

Each series of tests starts at 2.00 p.m. For each test product, severalseries of measurements were made on batches of 3 animals, each valueindicated being the average of 1 or more batches of 3 animals.

The following values were measured:

FAT: falling-asleep time equal to the time required to pass from thestate of active wakefulness to a non-alert state;

ST: sleep time, equal to the duration of the period of sleep rangingfrom falling asleep to waking up;

Sedation time: sum of the various times of active wakefulness during theobservation period of 120 minutes.

                  TABLE IV                                                        ______________________________________                                                 DOSE      FAT       ST     Sedation time                               COMPOUND (μM/100 g) (minutes) (minutes) (minutes)                        ______________________________________                                        1        2         5-8       55-85  80-95                                       2  2 4-5 49-92 89-97                                                          4  2 6-7 55-97 -95-102                                                        6  2  5-10 70-75 75-90                                                        9  2 NA-15   0-30 37-60                                                       16   2 13-15 20-45 38-73                                                      20   2 4-5 25-68 40-68                                                        21   2 5-7 70-75 75-87                                                        Melatonin 2 NA 0  65-105                                                      Diazepam 2 2-5  81-100  95-115                                                Placebo 0 NA 0 30-65                                                        ______________________________________                                         NA = not applicable, the animals remain alert.                           

The results obtained show, for the derivatives according to theinvention, a higher hypnotic effect than that of the reference products(melatonin) and equivalent to that of diazepam.

The derivatives according to the invention are thus particularlyadvantageous for the treatment of diseases associated with disorders ofmelatonin activity.

The present invention thus relates to the derivatives of general formulaI, as defined above, for their therapeutic use, in particular for thetreatment of depression and psychiatric disorders, in particular stress,anxiety, depression, insomnia, schizophrenia, psychosis and epilepsy,and also for the treatment of sleeping disorders associated withtravelling ("jet lag"), neurodegenerative diseases of the centralnervous system such as Parkinson's disease or Alzheimer's disease, forthe treatment of cancers, or alternatively as a contraceptive or as ananalgesic.

The melatonin analogues according to the invention are also useful forthe treatment of benign hyperplasia of the prostate, skin cancers, skincomplaints such as psoriasis and acne, mycosis and glaucoma, as well asfor increasing immune resistance.

They are also useful for preventing the symptoms of menopause,pre-menstrual syndromes, effects of ageing and sudden death syndrome inthe newborn.

They are also useful in veterinary application to regulate birth inruminants.

The present invention thus also relates to the pharmaceuticalcompositions adapted for administration of the derivatives of generalformula I, in particular via the oral, parenteral or rectal route, inthe form of wafer capsules, tablets, gelatin capsules, drinkablesolutions, injectable solutions, including delay forms andsustained-release dressings for transdermal administration of the activeprinciple, nasal sprays, or topical formulations (cream, emulsion,etc.), comprising a derivative of general formula I according to theinvention and at least one pharmaceutically acceptable excipient.

The pharmaceutical compositions according to the invention areadvantageously dosed to deliver the active principle in a single"intake".

For an oral administration, the effective unit doses are between 0.1 μgand 500 mg.

For an intravenous administration, the effective unit doses are between0.1 μg and 100 mg.

The melatoninergic analogues according to the invention are also usefulin cosmetics, in particular for protecting the skin against ageing, andalso against hair loss.

The present invention thus also relates to a cosmetic compositioncomprising a derivative of general formula I according to the invention.

The cosmetic compositions according to the invention are formulated in amanner which is suitable for their topical application, in particular inthe form of salves, creams, emulsions, ointments, lotions, etc.

What is claimed is:
 1. A compound of general formula I ##STR30## inwhich W represents an oxygen or sulphur atom or a group ═NR₁₂, whereinR₁₂ is a hydrogen atom or a lower alkyl, aryl, lower aralkyl orcycloalkyl group,X represents a divalent group of formula N--R7, whereinR7 is an acyl group, YZ represents a group of formula CR8═C, orCW--CR₁₉, wherein W has the same definition as above, or CR₂₀ R₂₁ --CR₁₉n represents an integer between 1 and 4, R1 to R6 and R19 to R21represent, independently of each other, a hydrogen atom, a hydroxylgroup or a lower alkyl, cycloalkyl, lower alkoxy, aryloxy, loweraralkoxy, lower alkylthio, arylthio, lower aralkthio, halo or nitrogroup or an unsaturated aliphatic, lower alkenyl, lower alkinyl, loweralkyl, aryl or aralkyl chain, each optionally substituted with one ormore hydroxyls, with one or more halogens, a lower perhaloalkyl group,an amino, lower alkylamino, lower-dialkylamino, arylamino, diarylamino,arylalkylamino or arylalkylamino group, a group of the form CV--R₁₁, orQCVR₁₁, in which V represents an oxygen or sulphur atom or an iminegroup ═N--R₁₂, and R₁₁ has one of the meanings of R₁, Q represents anoxygen or sulphur atom provided that R20 and R21 cannot simultaneouslybe a hydroxyl group, or an amine, or a hydroxyl and an amine, a hydroxyland a halogen, or a hydroxyl and an alkoxy, R8 has one of the meaningsof R1 or may also represent a halogen atom, or a group Q--CV--R11 inwhich Q, V, and R11 are as defined above, and R5 and R6 together canoptionally form part of a ring comprising--(CH₂)_(m) --CW--, wherein mis an integer between 2 and 3, and W is defined as above, provided thatat least one of R1, R6, R7 or R8, R20, and R21 represents a loweralkylcarbonyl group or a lower alkylthiocarbonyl;their racemic mixtures,their pure enantiomers or their mixtures in all proportions, and theirtherapeutically acceptable salts.
 2. A compound of general formula I##STR31## in which W represents an oxygen or sulphur atom or a group═NR₁₂, wherein R₁₂ is a hydrogen atom or a lower alkyl, aryl, loweraralkyl or cycloalkyl group,X represents a divalent group of formulaN--R7, Z represents a carbon atom, Y represents an acyl group or CR8,wherein R8 is an acyl group, n represents an integer between 1 and 4, R1to R6 and R19 to R21 represent, independently of each other, a hydrogenatom, a hydroxyl group or a lower alkyl, cycloalkyl, lower alkoxy,aryloxy, lower aralkoxy, lower alkylthio, arylthio, lower aralkthio,halo or nitro group or an unsaturated aliphatic, lower alkenyl, loweralkinyl, lower alkyl, aryl or aralkyl chain, each optionally substitutedwith one or more hydroxyls, with one or more halogens, a lowerperhaloalkyl group, an amino, lower alkylamino, lower-dialkylamino,arylamino, diarylamino, arylalkylamino or arylalkylamino group, a groupof the form CV--R₁₁ or QCVR₁₁, in which V represents an oxygen orsulphur atom or an imine group ═N--R₁₂, and R₁₁ has one of the meaningsof R₁, Q represents an oxygen or sulphur atom provided that R20 and R21cannot simultaneously be a hydroxyl group, or an amine, or a hydroxyland an amine, a hydroxyl and a halogen, or a hydroxyl and an alkoxy, R7has one of the meanings of R1 except that it cannot be hydroxyl, but itcan represent the group SO₂ R₂₆, wherein R₂₆ is an alkyl or a lowerhaloalkyl group, and R5 and R6 together can optionally form part of aring comprising --(CH₂)_(m) --CW--, wherein m is an integer between 2and 3, and W is defined as above, provided that at least one of R1, R6,R7 or R8, R20, and R21 represents a lower alkylcarbonyl group or a loweralkylthiocarbonyl;their racemic mixtures, their pure enantiomers ortheir mixtures in all proportions, and their therapeutically acceptablesalts.
 3. A compound of general formula I ##STR32## in which Wrepresents an oxygen or sulphur atom or a group ═NR₁₂, wherein R₁₂ is ahydrogen atom or a lower alkyl, aryl, lower aralkyl or cycloalkylgroup,X represents a divalent group of formula N--R7, YZ represents agroup of formula CR8═C, or CW--CR₁₉, wherein W has the same definitionas above, or CR₂₀ R₂₁ --CR₁₉ n represents an integer between 1 and 4, R1to R5 and R19 to R21 represent, independently of each other, a hydrogenatom, a hydroxyl group or a lower alkyl, cycloalkyl, lower alkoxy,aryloxy, lower aralkoxy, lower alkylthio, arylthio, lower aralkthio,halo or nitro group or an unsaturated aliphatic, lower alkenyl, loweralkinyl, lower alkyl, aryl or aralkyl chain, each optionally substitutedwith one or more hydroxyls, with one or more halogens, a lowerperhaloalkyl group, an amino, lower alkylamino, lower-dialkylamino,arylamino, diarylamino, arylalkylamino or arylalkylamino group, a groupof the form CV--R₁₁ or QCVR₁₁, in which V represents an oxygen orsulphur atom or an imine group ═N--R₁₂, and R₁₁ has one of the meaningsof R₁, Q represents an oxygen or sulphur atom provided that R20 and R21cannot simultaneously be a hydroxyl group, or an amine, or a hydroxyland an amine, a hydroxyl and a halogen, or a hydroxyl and an alkoxy, R6is an acyl group, which together with R5 can optionally form part of aring comprising --(CH₂)_(m) --CW--, wherein m is an integer between 2and 3, and W is defined as above, provided that at least one of R1, R7,or R8, R20, and R21 represents a lower alkylcarbonyl group or a loweralkylthiocarbonyl, R7 has one of the meanings of R1 except that itcannot be hydroxyl, but it can represent the group SO₂ R₂₆, wherein R₂₆is an alkyl or a lower haloalkyl group, and R8 has one of the meaningsof R1 or may also represent a halogen atom, or a group Q--CV--R11 inwhich Q, V, and R11 are as defined above;their racemic mixtures, theirpure enantiomers or their mixtures in all proportions, and theirtherapeutically acceptable salts.
 4. The compound according to claims 1,2, or 3, wherein at least one of the substituents R2 or R3 is not ahydrogen atom.
 5. The compound according to claims 1, 2, or 3, whereinR1 and R4 represent a hydrogen atom.
 6. The compound according to claims1, 2, or 3, wherein R5 is selected from the group consisting of loweralkyl, perfluoromethyl, perfluoroethyl, and perfluoropropyl groups. 7.The compound according to claims 1, 2, or 3, wherein R7 represents alower alkylcarbonyl group.
 8. The compound according to claims 1, 2, or3, wherein --YZ-- represents a group of formula CR8═C and R8 representsa hydrogen atom or a lower alkylcarbonyl group.
 9. A method of using thecompound according to claims 1, 2, or 3 for treating diseases associatedwith disorders of melatonin activity, said method comprising the step ofadministering said compound to a patient.
 10. A pharmaceuticalcomposition, comprising a compound according to claims 1, 2, or 3 and atleast one pharmaceutically acceptable excipient.
 11. A cosmeticcomposition, comprising a compound according to claims 1, 2 or 3, in aform of a cream, a salve, an emulsion, an ointment, or a lotion.
 12. Thecompound according to claims 1, 2, or 3, wherein n is
 2. 13. Thecompound according to claims 1, 2, or 3, wherein the lower haloalkylgroup is CF₃.
 14. The compound according to claims 1, 2, or 3, whereinthe halogen atom is selected from the group consisting of chlorine,bromine, iodine, and fluorine.
 15. The compound according to claim 4,wherein at least one of the substituents R2 or R3 represents a hydroxylor a lower alkoxy group.
 16. The compound according to claim 15, whereinthe group is a methoxy group.
 17. The compound according to claim 6,wherein the lower alkyl group is methyl or ethyl.
 18. The compoundaccording to claim 6, wherein R5 is perfluoroethyl.
 19. The compoundaccording to claims 1, 2, or 3, selected from the group consistingof:N-(2-(1-acetyl-5-methoxyindol-3-yl)ethyl)acetamide;N-(2-(2-acetyl-5-methoxyindol-3-yl)ethyl)acetamide;N-(2-(2-acetyl-5-methoxyindol-3-yl)ethyl)propionamide;N-(2-(5-methoxyindol-3-yl)ethyl)diacetamide;N-(2-(5-acetylindol-3-yl)ethyl)acetamide;N-(2-(1-acetyl-2-oxo-5-methoxy-2,3-dihydroindol-3-yl)ethyl)acetamide;N-(2-(5-methoxyindol-3-yl)ethyl)glutarimide;N-(2-(2-cyclohexylcarbonyl-5-methoxyindol-3-yl)ethyl)acetamide;N-(2-(2-acetyl-5-methoxyindol-3-yl)ethyl)diacetamide;N-(2-(1-acetyl-5-methoxyindol-3-yl)ethyl)diacetamide;N-(2-(5-methoxyindol-2-oxo-2,3-dihydroindol-3-yl)ethyl)glutarimide;[N-(2-(6-acetyl-5-methoxyindol-3-yl)ethyl)acetamide;]N-(2-(6-acetyl-1-carbethoxy-5-methoxyindol-3-yl)ethyl)acetamide;N-(2-(1-carbethoxy-2-acetyl-5-methoxyindol-3-yl)ethyl)acetamide;N-(2-(2-acetyl-6-ethyl-5-methoxyindol-3-yl)ethyl)acetamide;N-(2-(1-acetyl-5-methoxyindolin-3-yl)ethyl)acetamide;N-(2-(1-acetyl-6-chloro-5-methoxyindolin-3-yl)ethyl)acetamide;N-(2-(1-benzyloxycarbonyl-5-methoxyindolin-3-yl)ethyl)diacetamide;N-(2-(1-trifluoromethanesulphonyl-5-methoxyindolin-3-yl)ethyl)diacetamide;N-(2-(6-(1-acetyl-3-(N,N-diacetyl-2-aminoethyl)-5-methoxyindolin-2-yl)-5-methoxyindol-3-yl)ethyl)diacetamide;and N-(2-(carbethoxy-2-acetyl-5-methoxyindolin-3-yl)ethyl)acetamide. 20.A process for preparing the compound of claim 1, said process comprisingreacting a compound of general formula II, ##STR33## or a correspondinghalide, anhydride, or acid, with an acylating agent containing the group

    --CW--R5,

wherein W is an oxygen atom and X, Y, Z, n, R1 to R6 are defined as inclaim
 1. 21. A process for preparing the compound of claim 3, saidprocess comprising reacting a compound of general formula II, ##STR34##or a corresponding halide, anhydride, or acid, with an acylating agentcontaining the group

    --CW--R5,

wherein W is an oxygen atom and X, Y, Z, n, R1 to R6 are defined as inclaim
 2. 22. A process for preparing the compound of claim 3, saidprocess comprising reacting a compound of general formula II, ##STR35##or a corresponding halide, anhydride, or acid, with an acylating agentcontaining the group

    --CW--R5,

wherein W is an oxygen atom and X, Y, Z, n, R1 to R6 are defined as inclaim
 3. 23. A process for preparing the compound of claims 1, 2, or 3wherein R5 and R6 together form part of a ring comprising --(CH₂)_(n)--CW--, wherein W is an oxygen atom, said process comprising:(a)reacting a compound of general formula II, ##STR36## with an acylatingagent containing the group --(CH₂)--CW--O--alkyl, wherein W is an oxygenatom and n is an integer between 1 and 4 and wherein R6 represents ahydrogen atom; (b) converting the resulting acylated compound into anamide; and (c) cyclizing the amide.
 24. The process according to claim23, wherein the amide is subjected to acid catalysis in xylene in thepresence of a sufficient amount of para-toluenesulphonic acid to cyclizethe amide.
 25. A process for preparing the compounds of claims 1, 2, or3 in which W represents a sulphur atom, said process comprising reactinga compound of general formula I, ##STR37## with a sulphurizationreagent, wherein W is an oxygen atom.
 26. The process of claim 25,wherein the sulphurization agent is phosphorus pentasulphide orLawesson's reagent.
 27. A process for preparing the compounds of claim 1in which R6 is a hydrogen atom and Y--Z is a group of the formula,##STR38## wherein R8 is a group of formula ##STR39## said processcomprising hydrolyzing a compound of general formula III, ##STR40##wherein Y, n, and R1 to R5 are defined as in claim 1, R9 and R10represent a hydrogen atom or a lower alkyl residue, or R9 and R10together form a cycloalkyl group.
 28. A process for preparing thecompounds of claim 2 in which R6 is a hydrogen atom and Y--Z is a groupof the formula, ##STR41## wherein R8 is a group of formula ##STR42##said process comprising hydrolyzing a compound of general formula III,##STR43## wherein Y, n, and R1 to R5 are defined as in claim 2, R9 andR10 represent a hydrogen atom or a lower alkyl residue, or R9 and R10together form a cycloalkyl group.
 29. A process for preparing thecompounds of claim 3 in which R6 is a hydrogen atom and Y--Z is a groupof the formula, ##STR44## wherein R8 is a group of formula ##STR45##said process comprising hydrolyzing a compound of general formula III,##STR46## wherein Y, n, and R1 to R5 are defined as in claim 21, R9 andR10 represent a hydrogen atom or a lower alkyl residue, or R9 and R10together form a cycloalkyl group.